A Study of CyBorD (Cyclophosphamide, Bortezomib, Dexamethasone) Plus Daratumumab in People With Monoclonal Gammopathy of Renal Significance (MGRS)

Inclusion Criteria:

Inclusion criteria for cast nephropathy associated with MM:

• Subjects must have a confirmed diagnosis of NDMM as per standard IMWG criteria

• Subjects must have measurable disease, defined as meeting at least 1 of thefollowing criteria ≤ 14 days prior to registration:

• A monoclonal Immunoglobulin (M-protein) concentration on serum proteinelectrophoresis (SPEP) of ≥ 0.5 g/dL.

• Measurable urinary light chain secretion by quantitative analysis using urineprotein electrophoresis (UPEP) of ≥ 200 mg/24 hours.

• Involved serum free light chain (FLC) level ≥ 10 mg/dL, provided the serum FLCratio is abnormal.

• eGFR must be <40 ml/min/1.73m2

• Subjects must have histologically confirmed diagnosis of monoclonal gammopathyassociated CN by kidney biopsy OR If a kidney biopsy is not available, a percentageof urine albumin excretion (%UAE) < 25 % AND FLC > 50 mg/dL

Inclusion criteria for other MGRS associated renal diseases

• Histologically confirmed diagnosis of MGRS-associated renal disease by kidney biopsy

• Presence of monoclonal gammopathy by serum protein electrophoresis, Immunofixation,or Free Light Chain Assay

• Evidence of plasma cell dyscrasia by bone marrow biopsy confirming clonal plasmacell population

• eGFR <40 ml/min/1.73m2 or 24h urine total protein > 1gm

Inclusion criteria for both cast nephropathy associated with MM and other MGRS associated renal diseases

• Subjects must be ≥ 18 years of age at time of registration.

• Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance statusof 0, 1, or 2 ≤ 14 days prior to registration.

• No evidence of unequivocal recent nephrotoxic exposure (NSAIDs, radiocontrast…)

• No evidence of obstructive nephropathy by ultrasound

• Subjects must have adequate hematology laboratory values within 14 days prior toregistration defined by the following:

• Neutrophils ≥ 1.0 × 10^9 /L (Patients cannot have received G-CSF or GM-CSFwithin 1 week of screening or pegfilgrastim within 2 weeks of screening to meeteligibility).

• Platelets ≥ 100 × 10^9 /L for run-in and 75 × 10^9 /L for phase II (Note:Platelet support is not permitted to help participants meet eligibilitycriteria).

• hemoglobin ≥ 7.5 g/dL without prior red blood cells [RBC] transfusion within 7days before the laboratory test; recombinant human erythropoietin use ispermitted.

• Subjects must have adequate hepatic function laboratory values ≤ 14 days prior toregistration:

• Aspartate aminotransferase (AST), alkaline phosphatase (AP) or alanineaminotransferase (ALT) ≤ 3 × the upper limit of normal (ULN)

• Total bilirubin ≤ 1.5 x ULN except for patients with a history of elevatedtotal bilirubin, such as in Gilbert's.

• Hepatic Child-Pugh score at worse A (patients are eligible for the phase 2 partbut not for the Run-in-Period of the trial).

• Female patients will have to satisfy the following criteria:

• Be postmenopausal for at least 1 year Prior to registration visit, OR

• Be surgically sterile, OR

• If of childbearing potential, agree to practice 2 effective methods ofcontraception, at the same time, from the time of signing the informed consentform through 90 days after the last dose of study drug, OR

• Agree to practice true abstinence when this is in line with the preferred andusual lifestyle of the subject. (Periodic abstinence [e.g., calendar,ovulation, symptothermal, post-ovulation methods] and withdrawal are notacceptable methods of contraception). If patient is female and of childbearingpotential, she must have a negative serum beta human chorionic gonadotropin (β-HCG) test < 14 days prior to registration and consent to ongoing pregnancytesting during the course of the study.

• Male patients, even if surgically sterilized (i.e., status post-vasectomy), mustagree to one of the following

• Practice effective barrier contraception during the entire study treatmentperiod and through 90 days after the last dose of study drug, OR

• Practice true abstinence when this is in line with the preferred and usuallifestyle of he subject. (Periodic abstinence [e.g., calendar, ovulation,symptothermal, postovulation methods] and withdrawal are not acceptable methodsof contraception).

• Subjects must have the willingness and ability to comply with scheduled visits,treatment plan, laboratory tests, study procedures, and research procedures.

Exclusion Criteria:

• MGRS associated with diseases other than plasma cell dyscrasia (e.g. CLL, B-cellneoplasm, Waldenstrom's macroglobulinemia…)

• Plasma cell leukemia, AL amyloidosis, or POEMS syndrome.

• Treatment with prior drugs aimed at the plasma cell dyscrasia.

• Treatment with prior or concurrent investigational agents aimed at the plasma celldyscrasia.

• Female patients who are lactating or have a positive serum pregnancy test during thescreening period.

• Major surgery ≤ 14 days before registration.

• Focal radiation therapy within 14 days prior to registration with the exception ofpalliative- radiotherapy for symptomatic management but not on measurableextramedullary plasmacytoma.

• Disease-related central nervous system involvement.

• The subject has uncontrolled significant intercurrent illness including, but notlimited to, ongoing or active infection.

• Clinically significant cardiac disease, including:

• Myocardial infarction within 6 months before randomization, or unstable oruncontrolled disease/condition related to or affection cardiac function (e.g.,unstable angina, congestive heart failure, New York Heart Association ClassIII-IV)

• Uncontrolled cardiac arrhythmia

• Any serious medical or psychiatric illness that could, in the investigator'sopinion, potentially interfere with the completion of treatment according to thisprotocol.

• Known allergy to any of the study medications, their analogues, or excipients in thevarious formulations of any agent.

• Concurrent malignancy except for treated non-melanoma skin cancer, cervicalcarcinoma in situ and low-risk prostate CA being monitored without treatment.

• Grade 2 or higher peripheral neuropathy on clinical examination during the screeningperiod.

• Chemotherapy ≤ 14 days of registration.

• Exposure to an investigational drug (including investigational vaccine) or invasiveinvestigational medical device for any indication within 4 weeks or 5pharmacokinetic halflives, whichever is longer.

• Patients with known chronic obstructive pulmonary disease (COPD) with a forcedexpiratory volume in 1 second (FEV1) <50% of predicted normal; moderate or severepersistent asthma within the past 2 years. Note that FEV1 testing is required forparticipants suspected of having COPD and participants must be excluded if FEV1 is <50% of predicted normal

• Moderate or severe persistent asthma within the past 2 years, or uncontrolled asthmaof any classification. Note that participants who currently have controlledintermittent asthma or controlled mild persistent asthma are allowed to participate.

• Patients who have a contraindication to the use of any form of anticoagulation orantiplatelet agents.

• The use of strong CYP3A4 and CYP1A2 inducers or inhibitors will not be allowed whilepatients are treated on this study.

• Patients with Hepatic Child-Pugh score B and C. Note that patients with HepaticChild-Pugh score A are excluded from the Run-in-Period of the trial

• Patient is:

• Known history of human immunodeficiency virus (HIV) and those who areseropositive for HIV.

• Seropositive for hepatitis B (defined by a positive test for hepatitis Bsurface antigen [HBsAg]). Subjects with resolved infection (ie, subjects whoare HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must bescreened using real-time polymerase chain reaction (PCR) measurement ofhepatitis B virus (HBV) DNA levels. Those who are PCR positive will beexcluded. EXCEPTION: Subjects with serologic findings suggestive of HBVvaccination (anti-HBs positivity as the only serologic marker) AND a knownhistory of prior HBV vaccination, do not need to be tested for HBV DNA by PCR.

• Seropositive for hepatitis C (except in the setting of a sustained virologicresponse [SVR], defined as aviremia at least 12 weeks after completion ofantiviral therapy).

• Vaccination with live attenuated vaccines within 4 weeks of first study agentadministration.

• Plasmapheresis within 28 days before randomization.